The Structure Confirmation Of Anti-HBV Agent Enticavir And The Synthesis Of Its Diastereomer

Entecavir, developed by Bristol-Myers Squibb Co., was a novel carbocyclic 2’-deoxyguanosine analog, which can effectively inhibit the hepatitis B virus replication. This dissertation confirmed the structure of Entecavir through various means of detection and reported a new route for the synthesis of its （1R,3R,4S）-diastereomer.Because Entecavir is a complex compound with three chiral centers, we demonstrated its chemical structure and its stereo structure . Through a comprehensive analysis of the Entecavir synthetic route, we found that the main possible existing stereo isomers of Entecavir were enantiomer and （1R,3R,4S） -diastereomer . By configuration control of compounds C, the enantiomers of existence was eliminated; meanwhile, （1R,3R,4S） - diastereomer was synthesized and the stereo structure of Entecavir was further demonstrated by HPLC-MS detection. The above structure demonstration method for the complex drug with three chiral centers hasn’t been reported before, which passed the examination of ShangHai Food&Drug Administration and provided a new standard of the quality control for the treatment of hepatitis B drug Entecavir after its domestic listing.Based on the literatures and the experience, we designed a new route for the synthesis of its （1R,3R,4S）- diastereomer. This route started from （1S,2R）-2-[（benzyloxy）methyl]-3-cyclopenten-l-ol, ingeniously used Mitsunobu reaction and the epoxy stereotactic effect of t-BuOOH/VO（acac）₂ reaction, successfully obtained the important intermediate B’of synthsis （1R,3R,4S）-diastereomer. Then through benzyl protection, bimolecular nucleophilic substitution reactions, p-methyoxyphenyldiphenylmethyl protection, Dess-Martin oxidation, methylenation, benzyl and p-methyoxyphenyldiphenylmethyl of guanosine deprotection and two benzyl deprotection, the target product is obtained.